Essential Proteins for Mitochondrial Function

The mitochondrial and nuclear genomes encode mitochondrial membrane proteins. Nuclear-encoded proteins need to pass the outer membrane (OM) through the central entry gate, the translocase of the outer membrane (TOM complex). The OM also comprises of the sorting and assembly machinery (SAM complex) needed for the biogenesis of OM proteins.

Different sorting pathways are followed by precursor proteins. The carrier translocase of the IM (TIM22 complex) mediates the insertion of proteins with internal signal sequences to the inner membrane (IM).

Matrix-targeted and inner membrane-sorted pre-proteins with cleavable N-terminal presequences are directed to the translocase of the IM (TIM23 complex). ATP-driven pre-sequence translocase-associated motor (PAM) is needed for translocation of pre-protein domains across the IM.

Mitochondrial DNA encodes a small number of IM proteins. Oxa1 is the primary insertase and, along with Mdm38 and Mba1, binds ribosomes and inserts proteins into the IM. Intermembrane space proteins (IMS) with cysteine motifs need the machinery for import and assembly (MIA) in the mitochondrial IMS.

Mitochondrial import protein pathway.

Figure 1. Mitochondrial import protein pathway.

Mitochondrial fission and fusion

Mitochondria reside in a dynamic network within living cells, undergoing fission and fusion events that help IM and OM fusion and the exchange of organelle contents.

Mitochondrial fusion relies on the action of three large GTPases: mitofusins (Mfn1 and Mfn2) mediating membrane fusion on the OM level, and Opa1 which is crucial for the fusion of inner mitochondrial membrane (IMM).

The local organization of Fis1 and recruitment of GTPase DRP1 are required for mitochondrial fission for the fission machinery assembly that subsequently causes membrane scission.

Mitochondrial fusion and fission pathways.

Figure 2. Mitochondrial fusion and fission pathways.


Mitophagy is a process in which damaged mitochondria are selectively removed by autophagosomes and subsequently catabolized by lysosomes.

Differentiating the healthy mitochondria from the damaged mitochondria (with depolarized mitochondrial membrane potential) is the first stage of quality control by mitophagy. They are told apart by the buildup of PTEN induced putative kinase 1 (PINK1) subsequent to mitochondrial membrane depolarization of damaged mitochondria.

In healthy mitochondria, PINK1 is processed by the rhomboid-like protein localized in the mitochondrial IM called PARL. After importing and inserting the newly synthesized PINK1 in the cytosol into the mitochondrial IM, PARL cleaves PINK1 in its putative transmembrane domain to produce the 52 kDa form of PINK1. A proteasome-dependent pathway rapidly removes the processed form of PINK1 likely following its release from the mitochondrial IMS into the cytosol.

The depolarization of the mitochondrial membrane potential may inhibit the IM insertion and subsequent processing of PINK1 by PARL, causing the accumulation of the full-length PINK1 in the mitochondrial OM, likely facing the cytosol. The buildup of PINK1 with kinase activity is enough for the recruitment of Parkin to the mitochondrial surface.

Mitophagy pathway.

Figure 3. Mitophagy pathway.

Parkin recruitment is followed by mitophagy induction which involves the Parkin-mediated ubiquitination of mitochondrial substrates, prominently displaying Lys63-linked polyubiquitin chains, often associated with signaling. Various Parkin substrates are identified in mitochondria: the mitofusin mitochondrial assembly regulatory factor (MARF), mitofusin 1, mitofusin 2 and voltage-dependent anion-selective channel protein 1 (VDAC1), all of which are embedded in the OM.

Parkin encourages the recruitment of the ubiquitin-binding adaptor known as p62 (also called sequestosome 1). The p62 protein is capable of aggregating ubiquitinated proteins by polymerizing with other p62 molecules and recruiting ubiquitinated cargo into autophagosomes by attaching to LC3.

p62 builds up on mitochondria, attaches to Parkin-ubiquitinated mitochondrial substrates, mediates clumping of mitochondria, and binds ubiquitinated substrates to LC3 to help the autophagic deterioration of ubiquitinated proteins. The histone deacetylase HDAC6 also accumulates on mitochondria after Parkin translocation, binds ubiquitinated substrates, and is essential for Parkin-mediated mitophagy.

In the cytosol, LC3 is synthesized as proLC3. Following its translation, proLC3 is immediately cleaved by Atg4B to expose the carboxyterminal Gly of LC3 (LC3-l). The same E1-like enzyme, Atg7, activates LC3-l, which is then transferred to Atg3 (a second E2-like enzyme) and conjugated to PE (phosphatidyl-ethanolamine). The LC3-PE conjugate is called LC3-II, which is an autophagosome membrane-bound form of LC3. The Atg12-Atg5 conjugate acts as an E3-like ligase for LC3 lipidation.

Once the isolation membrane is formed, it subsequently elongates to engulf mitochondria. When the isolation membrane is elongated, the localization of the Atg5-Atg12=Atg16L complex to the membrane takes place, forming a cup-shaped structure. When LC3-II localizes to the isolation membrane, the Atg5-Atg12=Atg16L complex dissociates from the membrane.

Following the formation of autophagosome, its outer membrane fuses with lysosomes to produce autolysosomes. The autolysosome formation is then followed by the degradation of the intra-autophagosomal contents by the lysosomal hydrolases, including lipases and cathepsins, and the degradation of LC3-II on the intra-autophagosomal surface by cathepsins.


  • Becker T, Gebert M, Pfanner N and van der Laan M (2009). Biogenesis of mitochondrial membrane proteins. Curr Opin Cell Biol, 21(4): 484-93.
  • Chacinska A, Koehler CM, Milenkovic D, Lithgow T, and Pfanner N (2009). Importinging mitochondrial proteins: machineries and mechanisms. Cell, 138(4): 628-44.
  • Chen H, and Chan DC (2006). Critical dependence of neurons on mitochondrial dynamics. Curr Opin Cell Biol, 18(4): 453-9.
  • Hyde BB, Twig G, and Shirihai OS (2010). Organellar vs cellular control of mitochondrial dynamics. Semin Cell Dev Biol, 21(6): 575-81.
  • Imai Y, and Lu B (2011). Mitochondrial dynamics and mitophagy in Parkinson's disease: disordered cellular power plant becomes a big deal in a major movement disorder. Curr Opin Neurobiol, 21(6): 935-41.
  • Jin SM and Youle RJ (2012). PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci, 125(Pt4): 795-9.
  • Lee J, Giodano S and Zhang J (2012). Autophagy, mitochondria and oxidative stress: cross-talk and redox signaling. Biochem J, 441(2): 523-40.
  • Scott I, and Youle RJ (2010). Mitochondrial fission and fusion. Essays Biochem,47: 85-98.
  • Tanida I (2011). Autophagosome formation and molecular mechanism of autophagy. Antioxid Redox Signal, 14(11): 2201-14.
  • Twig G, Hyde B, Shirihai OS (2008). Mitochondrial fusion, fission and autophagy as a quality control axis: the bioenergetic view. Biochem Biophys Acta, 1777(9): 1092-7.
  • Vives-Bauza C and Prezedborski S (2011). Mitophagy: the latest problem for Parkinson's disease. Trends Mol Med, 17(3): 158-65.
  • Youle RJ, and Karbowski M (2005). Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol, 6(8): 657-63.
  • Youle RJ and Narenda DP (2011). Mechanisms of mitophagy. Nat Rev Mol Cell Biol, 12(1): 9-14.
  • Zungu M, Schisler J and Willis MS (2011). All the little pieces. -Regulation of mitochondrial fusion and fission by ubiquitin-like modifier and their potential relevance in the heart. Circ J, 75(11): 2513-21.

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Last updated: Apr 1, 2019 at 5:40 AM


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